ArticleExperimental hematology & oncology2025
Dickkopf-1 promotes tumor progression of gefitinib- resistant non-small cell lung cancer through cancer cell-fibroblast interactions.
Article in Experimental hematology & oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- DKK1 Promotes Cisplatin Resistance in Oral Squamous Cell Carcinoma via SLC3A2-Dependent Ferroptosis Suppression.Cancer reports (Hoboken, N.J.) · 2026Article
- Epigenetic Activation of the KDM6B-DKK1 Axis Promotes Colorectal Cancer Peritoneal Metastasis Through Wnt/β-Catenin-Associated EMT.Journal of cellular and molecular medicine · 2026Article
- DKK1 in Cancer: A Bench-to-Bedside Review of Molecular Mechanisms and Clinical Applications.Cancers · 2026Review
- The Dickkopf-1 (DKK1) Dichotomy in Oncology: New Insights on Tumor Progression and Immune Regulation.International journal of molecular sciences · 2026Review
- Immunomodulation by platelet-derived DKK1: potential for controlling disease and pathology in leishmaniasis and implications for other infectious diseases.Frontiers in immunology · 2026Review
- Article
- DKK1 Overexpression in Lung Adenocarcinoma: Prognostic Implications, Immune Microenvironment Correlates, and Regulatory Network Characterization.Biological procedures online · 2025Article
- Hidden forces: the impact of cancer-associated fibroblasts on non-small cell lung cancer development and therapy.Journal of translational medicine · 2025Review
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Authors and funding
6 authors.
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Abstract
backgroundCancer cell-secreted proteins play a critical role in tumor progression and chemoresistance by influencing intercellular interactions within the tumor microenvironment. Investigating the intratumoral functions of these secretory proteins may provide insights into understanding and treating chemoresistant cancers. This study aims to identify potential anticancer target(s) in gefitinib-resistant non-small cell lung cancer (NSCLC), with a focus on secretory proteins and their effects on intercellular interactions.
methodsDifferentially expressed secretory proteins were identified in gefitinib-resistant human NSCLC cell lines (PC9-GR and HCC827-GR), revealing an elevation in Dickkopf-1 (DKK1) expression and secretion. To elucidate the role of DKK1 in gefitinib-resistant cancer, the anticancer effects of a neutralizing antibody against DKK1 were evaluated in tumors comprising either cancer cells alone or cancer cells co-injected with human lung fibroblasts (MRC-5). Following the confirmation of the importance of cancer cell-fibroblast interactions in the protumorigenic activity of DKK1, the fibroblast traits modulated by DKK1 were further analyzed.
resultsGefitinib-resistant NSCLC cells exhibited increased DKK1 protein expression. Although elevated DKK1 levels were linked to poor prognosis, DKK1 did not directly affect cancer cell proliferation. However, DKK1 blockade showed significant anticancer effects in gefitinib-resistant tumors containing lung fibroblasts, suggesting that DKK1's pro-tumorigenic roles are mediated through cancer cell-fibroblast interactions. DKK1 altered fibroblast characteristics, enhancing inflammatory fibroblast traits while diminishing myofibroblast traits in tumor microenvironment. These DKK1-induced changes were mediated via activation of the c-JUN pathway in fibroblasts. Moreover, DKK1 was identified as a potential anticancer target across various cancer types beyond gefitinib-resistant lung cancer.
conclusionsThis study clarifies that DKK1 mediates interactions between cancer cells and fibroblasts in gefitinib-resistant lung cancer, contributing to tumor progression. Therefore, we propose DKK1 as a promising anticancer target for the treatment of gefitinib-resistant NSCLC.
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